Upper airways disease or rhinosinusitis are common disorders with over 33 million cases annually in the US. Both acute and chronic forms of sinusitis are common leading to over 12 million physician visits annually. Of rhinosinusitis sufferers, up to 500,000 people resort to sinus surgery in the U.S. each year. A recent epidemiological review (Vital Health Statistics, USA, 10:1999) ranks chronic rhinosinusitis as the most common chronic condition in the U.S. affecting more people than hypertension and asthma. It has been estimated that the annual cost of this condition in the US is $24 billion. These upper airways disorders are characterized by a variety of symptoms, including nasal congestion, facial pain and pressure, nasal discharge, and headaches.
Anatomically, the nasal passageways up to the soft palate and including the sinuses can be thought of as the upper airways or upper respiratory tract, while the larynx and below including the lungs, can be thought of as the lower airways or lower respiratory tract. The sinuses are four pairs of air-filled spaces, the ethmoid, maxillary, sphenoid, and frontal sinuses, located in the upper airways. The upper airways, including the sinuses, warm and humidify the air during breathing. The upper airways filter particles, such as bacteria, spores, and dust, from the air. Generally, the nasal passages contain bacteria, while the sinuses are sterile. The upper airways and sinuses are lined with a mucosal layer of epithelium, similar in most ways to the mucosal epithelium that lines the lower respiratory tract. The sinuses communicate with the rest of the upper airways through small orifices or ostium that may become obstructed leading to symptoms and disease.
Sinusitis and rhinitis causes inflammation which results in decreased perfusion of the upper airways by bodily fluids. These sites are difficult to reach with aerosols or systemic bioactive substances, as compared to other tissues. Larger systemic doses are required to deliver therapeutically effective amounts of bioactive agents to the upper airways, which increase the likelihood of adverse events. Moreover, inadequate dosing can lead to microbial resistance, spread of disease, and continued suffering of the subject. What are needed in the art are minimally invasive methods which improve the local delivery of a variety of bioactive agents to nasal passages and paranasal sinuses in order to more effectively and efficiently treat these disorders.
A typical process leading to acute sinusitis starts with a flu or cold virus. Viruses themselves do not usually cause sinusitis directly and are implicated in only about 10% of sinusitis cases. Instead, they set the stage by causing nonallergic inflammation and congestion in the upper airways (called rhinitis) that leads to obstruction. This creates an environment conducive to bacterial growth that can lead to upper airways infection. In fact, rhinitis is the precursor to sinusitis in so many cases that expert groups now refer to most cases of upper airways disease as rhinosinusitis (Guide to First-line Management. Kennedy (1994) Health Communications, Inc.).
The vast majority of rhinosinusitis is not allergic in its origins and is associated with increased levels of nonallergic proinflammatory cytokines such as IL-8, IL-1, and TNF. Rhinosinusitis is often associated with bacterial invasion of the upper airways leading to endotoxin release and increased TNF-alpha. Sun et al. showed that VEGF concentration was significantly higher in paranasal sinus effusions in response either endotoxin or TNF-alpha in biopsies from sinusitis subjects relative to controls. Viral infections can also modulate TNF mediated responses in the upper airways (Sun et al. Auris Nasus Larynx. 32(3):243-9 (2005)). Das et al. reported, the amplification of proinflammatory cytokines by respiratory syncytial virus infection in human nasal epithelial cells. RSV infection of nasal epithelial cell resulted in significant accumulations of interleukin IL-6, IL-8, and RANTES when compared with findings in control samples. These investigators concluded that RSV infection primes nasal epithelial cells to TNF, resulting in a hyperimmune response.
Frequently, rhinosinusitis sufferers will have nasal polyps. Polyps are benign masses of extra tissue that cause problems related to their size and location. Nasal and sinus polyps form commonly in severe or chronic disease and can obstruct drainage of the nose and sinuses, and in extreme instances, may even protrude from the nose. Nasal polyposis is also a nonallergic inflammatory condition of the nose and sinuses associated with chronic nonallergic rhinitis, aspirin intolerance, and nonallergic asthma (Holmberg et al. Clin. Exp. Allergy Suppl. 3:23-30 (1996)). For most subjects with nasal polyps, treatment consists of both medical and surgical management, as surgery cannot treat the underlying inflammatory component of the mucosal disease. Other conditions associated with nasal polyps are Churg-Strauss Syndrome, fungal sinusitis, and cilia dyskinetic syndrome, (Kartagener's) and Young Syndrome.
Historically, the treatment of rhinosinusitis has largely focused on addressing the symptoms of the condition through acute antibiotic therapy, intranasal or oral corticosteroids, and sinus surgery. While antibiotics are useful in treating the acute exacerbations of rhinosinusitis, antibiotics alone often do not eliminate the underlying often-chronic inflammation. Moreover, systemic antibiotics are often less effective because of poor tissue penetration associated with rhinosinusitis. Intranasal and oral corticosteroids, have been used extensively to reduce the inflammation that plays a critical role in rhinosinusitis, but corticosteroids can cause serious side effects including thinning of membranes, bleeding, growth retardation in children, and osteoporosis; and when possible must be avoided or cautiously used with patients that have certain conditions, such as gastrointestinal ulcers, renal disease, hypertension, diabetes, osteoporosis, thyroid disorders, and intestinal disease.
Anecdotally, some investigators describe patients who get relief of their sinus symptoms by flushing their nasal passages with saline. Symptomatic improvement is achieved by clearing mucus and hydrating thick secretions. It may also decrease blood flow resulting in decongestion, and infectious organisms are also removed with the nasal secretions. Many patients are asked to do this regularly after endoscopic surgery when catheters are available to facilitate flushing. Commercially available products include saline-filled squeeze atomizers, some of which contain the moisturizing agent glycerol. The nares may also be washed with the saline using a bulb or catheter-tipped syringe. Additionally, investigators have reported hypertonic saline can be beneficial for rehydration. Despite these reports, rehydrating and flushing agents do not treat the underlying inflammation in rhinosinusitis and other problems including pain, infection, viscous secretions, and polyps.
No convincing data exists to support the use of antihistamines and decongestants in rhinosinusitis. Some CF patients have been counseled to stay away from them for fear of further drying out secretions. Physicians report that still other CF subjects, especially those with a clear history of allergies, use antihistamines regularly with relief of symptoms of stuffiness and runny nose and no worsening of their lung congestion.
Decongestants, such as pseudoephedrine (Sudafed), can be helpful for relieving symptoms of sinus headache or fullness. Topical decongestants, such as oxymetazoline (AFRIN), can give temporary relief by promoting sinus drainage, but should not be used more than three consecutive days for fear of a rebound phenomenon leading to increased nasal secretions. Anticholinergic compounds can also be useful in drying and shrinking membranes.
Mucolytics, such as guaifenesin and N-acetyl cysteine depolymerize mucin molecules and may be used to promote sinus drainage and are thought not to be detrimental (Marks et al. Am. J. Rhinol. 11(1):11-4 (1997)). Numerous nucleases have been described. Nuclease can be divided into two classes, exonucleases and endonucleases, based on the positions of the cleaved bonds within the DNA or RNA polymers. One nuclease, DNase has a number of known utilities and has been used for therapeutic purposes. Its principal therapeutic use has been to reduce the viscoelasticity of pulmonary secretions in such diseases as pneumonia and cystic fibrosis, thereby aiding in the clearing of the lower respiratory airways (Lourenco et al. Arch. Intern. Med, 142:2299-2308 (1982); Shak et al. Proc. Natl. Acad. Sci., USA. 1990, vol. 87:9188-9192; and Hubbard et al. New England J. Medicine 326(12):812-815 (1992)). The utility of nucleases in rhinosinusitis is limited however because these agents do not decrease inflammation and nor do they treat the underlying etiologic agent.
Surgeries frequently used in rhinosinusitis to improve sinus drainage are rooted in the theory that the disease can be reversed by identifying and correcting the obstruction that caused the condition, but while such surgery usually offers temporary relief of symptoms, it is typically not curative.
Cystic Fibrosis (CF) affects the respiratory epithelium causing the inflammation and infection. Virtually all individuals with CF suffer from pansinusitis, inflammation, and infection of all their sinuses. Complication of sinusitis in CF can cause significant symptoms and in some cases may contribute to the worsening of lung disease (Ramsey et al. Allergy Clin. Immunol. 90:547-53 (1992); Lewiston et al. Transplant. Proc. 23:1207-8 (1991); Umetsu et al. Lancet 335:1077-8 (1990)).
The true incidence of sinusitis in CF is not known, but in reality, patients with cystic fibrosis always have chronic sinusitis. The great majority of patients with CF develop sinus symptoms, usually between the ages of 5 and 14 years (Stern et al. Am. J. Dis. Child. 136:1067-70 (1982)). Nasal polyps are the most distinctive of the physical findings. Polyps are benign masses of extra tissue that cause problems related to their size and location. Nasal and sinus polyps form commonly in CF and can obstruct drainage of the nose and sinuses, and in extreme instances, may even protrude from the nostrils. The prevalence of nasal polyps in CF has been reported as high as 48% and appears to be proportional to age (Brihaye et al. Int. J. Pediatr. Otorhinolaryngol 28:141-3 (1994); Coste Rhinology 33:152-3 (1995)).
It is generally accepted that there is some penetration of the sinuses with orally inhaled tobramycin for patients who use the drug regularly. Anecdotally, many CF patients have benefited from this form of treatment. However, commercial nebulizers are designed to produce aerosols with a particle distribution to maximize deposition of drug in the lower airways.
As in other subjects with rhinosinusitis, nasal steroids are used a mainstay of therapy for CF sufferers of rhinosinusitis also. There are reports that regular use of nasal steroids diminish the size and number of nasal polyps, and that use after polypectomy decreases the rate at which polyps reform (Hui et al. Eur. Arch. Otorhinolaryngol 252:191-6 (1995)).
The surgical options include placement of antrostomies, debridement of maxillary sinuses, ethmoidectomies, and nasal polypectomy. Surgical intervention may relieve nasal obstruction, decrease purulent nasal discharge, increase activity level, and improve olfaction (Nishioka et al. Orolaryngol. Head Neck Surg. 113:440-5 (1995)). In addition, sinus surgery without aggressive follow-up medical care, such as upper airway clearance measures or inhaled corticosteroids, is not useful (Mak et al. Clinical Reviews in Allergy and Immunology 21:51-63 (2001)).
Another major current limitation in treating rhinosinusitis is the inability to achieve sufficient drug levels in these inflamed tissues. While a variety of catheters, microcatheters and cannulae are used in procedures to deliver fluid, gas, suction and energy to select regions of the body, none have been employed effectively in treating rhinosinusitis. Existing catheters are typically straight or curved segments of rigid plastic or metal tubing attached to a connector. In the development of advanced less invasive methods to treat the rhinitis, sinusitis, and sino-nasal polyps, it is desired to have microcatheters that can access and be advanced into very small structures or the ostium of a paranasal sinus to perform minimally invasive procedures including the delivery of beneficial bioactive materials including therapeutics. What are needed are microcatheters that access curved or tortuous spaces such as the entrances to the various sinuses. Such a device will require a combination of flexibility and rigidity in order to be advanced to the target site, while maintaining a diameter in the range of 50 to 1500 microns.